Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival/resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors.
The PI3K signaling pathway is one of the prominent pathways that promote tumor cell survival. PI3K is activated by many cancer related receptor tyrosine kinases (e.g. PDGFR, EGFR, HER2/3, or IGF-1R), cell adhesion molecules, GPCR, and oncogenic proteins (such as Ras). The PI3K pathway activation by genetic alteration of PI3K (activation mutation and/or amplification) and/or loss-of-function of the tumour suppressor PTEN are frequently found in many tumors. Furthermore, activation of PI3K is one of the major mechanisms causing the resistance of tumors to radio-, chemo- and targeted therapeutics.
Once PI3K is activated, it catalyzes the generation of PIP3 from PIP2. The biological active PIP3 binds to the pleckstrin homology (PH) domains of PDK-1, AKT, and other PH-domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, these proteins are translocated to the cell membrane and are subsequently activated to induce tumor cell proliferation, survival, invasion and migration.
Fibroblast growth factors (FGFs) and their receptors (FGFRs) drive crucial developmental signaling pathways, which are responsible for many functions of the tumor cells, including cell proliferation, survival and migration through downstream signaling pathways mediated by PLCγ/PKC, RAS/MAPK, PI3K/AKT, and STATs. FGFR signaling pathways also regulate tumor stromal cells as well as tumor angiogenesis. There are several types of genetic evidence that support an oncogenic function of FGFRs: gene amplifications, activating mutations, chromosomal translocations and aberrant splicing at the post-transcriptional level.
Endometrial cancer (EC) is the most common gynecologic malignancy in industrialized countries, with an incidence rate of 12.9 per 100,000 women per year. Early-stage EC (stage I or II) can be effectively treated with surgery, while treatment of recurrent or high grade metastatic disease is limited to cytotoxic chemotherapy, e.g. paclitaxel and carboplatin. In addition, for recurrent EC, there are still no agreement and no definitive drugs of choice in spite of the poor prognosis of this subset of patients. It is noteworthy that the available chemotherapies do not provide long-term disease control, and many patients demonstrate intrinsic resistance and significant toxicities to these therapies. As such, it remains an important unmet medical need for recurrent EC. The successful management of these patients depends on the identification and understanding of molecular mechanisms underlying the initiation and progression of EC to achieve a more tailored therapy, based on the biological tumor profile.
As described in the present text, the anti-tumor efficacy of the PI3K inhibitor copanlisib was investigated in preclinical tumor models in vitro and in vivo in combination. The combination of the PI3K inhibitor copanlisib with FGFR inhibitors was found to be synergistic, which led to tumor regression in preclinical tumor model in vivo compared to tumor progression or tumor stasis in animals treated with monotherapy of each agent.
Unexpectedly, and this represents a basis of the present invention, when combinations of:                component A: a 2,3-dihydroimidazo[1,2-c]quinazoline compound of general formula (A1) or (A2), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein; with        component B: a substituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compounds of general formula (B), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein;        
were evaluated for the treatment of endometrial cancer (hereinafter abbreviated to “EC”), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis, synergistically increased anti-tumor activities were demonstrated with these combinations compared to each monotherapy, providing a fundamental rationale for the clinical combination therapy using PI3K inhibitors-FGFR inhibitors.
To the Applicant's knowledge, no generic or specific disclosure or suggestion in the prior art is known that either combinations of:
component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A1) or (A2), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
component B: one or more substituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compounds of general formula (B), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
in which optionally either or both of said components A and B of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, would be effective in the treatment or prophylaxis of cancer, particularly endometrial cancer (hereinafter abbreviated to “EC”), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis.
Based on the action of the testing compounds described in this invention, the combinations of the present invention as described and defined herein, show a beneficial effect in the treatment of cancer, particularly endometrial cancer (hereinafter abbreviated to “EC”), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis.
Accordingly, in accordance with a first aspect, the present invention relates: to combinations of:
component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A1) or (A2), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
component B: one or more substituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compounds of general formula (B), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
in which optionally either or both of said components A and B) of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with a second aspect, of the present invention relates to the use of any of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly endometrial cancer (hereinafter abbreviated to “EC”), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis.
Further, in accordance with a third aspect, the present invention relates to a kit comprising:
a combination of:
component A: one or more 2,3-dihydroimidazo[1,2-c]quinazoline compounds of general formula (A1) or (A2), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
component B: one or more substituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compounds of general formula (B), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
in which optionally either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
Further, in accordance with a fourth aspect, the present invention relates:                to use of biomarkers, such as the loss of tumor suppressor PTEN or FBXW7, either alone or in combination with another form of PI3K pathway activation selected from perturbation of any of the following alone or in combination: mutation in PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3 and/or FGFR4; PTEN-loss and alteration of PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3 and/or FGFR4 which may be measured at either the protein level, mRNA level, or DNA level,        
for predicting the sensitivity and/or resistance of a patient with endometrial cancer (hereinafter abbreviated to “EC”), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis, to a combination of a component A and a component B as defined herein, thus providing rationale-based dosage as defined herein to overcome said resistance of a patient with endometrial cancer (hereinafter abbreviated to “EC”), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis, to a combination of a component A and a component B as defined herein (patient stratification);
to a method of determining the loss of tumor suppressor PTEN or FBXW7; and
to a method for determining perturbations in PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3 and/or FGFR4. PTEN loss and alteration of PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3 and/or FGFR4.